Efficient separation of enantiomers of piperidone derivatives by precipitation of the desired eantiomer during in situ racemization of the unwanted enantiomer

Abstract

A process for dynamically separating the enantiomers of a piperidone derivative of formula (1)wherein:R1 is aryl optionally mono- to polysubstituted, heteroaryl, which is linked to the chiral center via at least one carbon atom of its own or a carbon atom belonging to the methylene bridge, or straight-chain or branched C1-C8-alkyl optionally mono- to polysubstituted by halogen;R2 and R3, which are identical or different, are each straight-chain or branched C1-C6-alkyl; andn is 0, 1, 2 or 3,the process comprising:(a) dissolving an optically active acid and optionally catalytic amounts of a sulfonic acid in a solvent to make a first solution maintained at a desired temperature;(b) adding a second solution of the piperidone derivative to the first solution to precipitate out the desired enantiomer of the piperidone derivative as a salt of the optically active acid used while racemizing the unwanted enantiomer of the piperidone derivative in solution and further precipitating the desired enantiomer of the piperidone derivative from the racemizing the unwanted enantiomer of the piperidone derivative in a dynamic process; and(c) separating the desired enantiomer of the piperidone derivative as a salt of the optically active acid.

We claim:  
     
       1. A process for dynamically separating the enantiomers of a piperidone derivative of formula (1)                    
       wherein: 
       R 1  is aryl optionally mono- to polysubstituted, heteroaryl, which is linked to the chiral center via at least one carbon atom of its own or a carbon atom belonging to the methylene bridge, or straight-chain or branched C 1 -C 8 -alkyl optionally mono- to polysubstituted by halogen;  
       R 2  and R 3 , which are identical or different, are each straight-chain or branched C 1 -C 6 -alkyl; and  
       n is 0, 1, 2 or 3,  
       the process comprising: 
       (a) dissolving an optically active acid and optionally catalytic amounts of a sulfonic acid in a solvent to make a first solution maintained at a desired temperature;  
       (b) adding a second solution containing the piperidone derivative to the first solution to precipitate out the desired enantiomer of the piperidone derivative as a salt of the optically active acid while racemizing the unwanted enantiomer of the piperidone derivative in solution and further precipitating the desired enantiomer of the piperidone derivative formed from the racemization of the unwanted enantiomer of the piperidone derivative in solution; and  
       (c) separating the desired enantiomer of the piperidone derivative as a salt of the optically active acid.  
     
     
       2. The process according to  claim 1 , wherein the desired enantiomer of the piperidone derivative of formula (1) has the formula (1a):                    
     
     
       3. The process according to  claim 1 , wherein: 
       R 1  is                    
       R 2  and R 3 , which are identical or different, are each methyl or ethyl;  
       R 4  independently of one another are methoxy, ethoxy, isopropyloxy, halogen, hydroxy, C 1 -C 6 -alkyl, which is partially or fully halogenated, trifluoromethyl, amino, nitro, cyano, benzoyl, or C 1 -C 6 -alkylcarbonyl;  
       n is 1; and  
       m is 0 or 1.  
     
     
       4. The process according to one of  claims 1  to  3 , wherein the optically active acid is ditoluoyltartaric acid or dibenzoyltartaric acid. 
     
     
       5. The process according to one of  claims 1  to  3 , wherein the optional sulfonic acid is toluenesulfonic acid or camphorsulfonic acid. 
     
     
       6. The process according to one of  claims 1  to  3 , wherein the solvent is selected from the group consisting of: acetone, acetonitrile, methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl acetate, water, toluene, methylcyclohexane, n-butyl acetate, and mixtures thereof. 
     
     
       7. The process according to  claim 6 , wherein the solvent is selected from the group consisting of: acetone, acetonitrile, and mixtures thereof. 
     
     
       8. The process according to one of  claims 1  to  3 , wherein the process is carried out at a temperature of between 35° C. and 70° C. 
     
     
       9. The process according to one of  claims 1  to  3 , wherein the process is carried out at a temperature of between 50° C. and 65° C. 
     
     
       10. The process according to one of  claims 1  to  3 , wherein the desired enantiomer is obtained with a purity of ≧95% ee. 
     
     
       11. The process according to  claim 1 , wherein: 
       R 1  is 2-methoxyphenyl;  
       R 2  and R 3  are each methyl;  
       n is 1.  
     
     
       12. The process according to  claim 1 , wherein 1 equivalent of optically active acid is used. 
     
     
       13. The process according to  claim 12 , wherein the optically active acid is ditoluoyltartaric acid or dibenzoyltartaric acid. 
     
     
       14. The process according to  claim 12 , wherein the solvent is selected from the group consisting of: acetone, acetonitrile, methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl acetate, water, toluene, methylcyclohexane, n-butyl acetate, and mixtures thereof. 
     
     
       15. The process according to  claim 12 , wherein the process is carried out at a temperature of between 35° C. and 70° C. 
     
     
       16. The process according to  claim 15 , wherein the process is carried out at a temperature of between 50° C. and 65° C. 
     
     
       17. The process according to  claim 16 , wherein the process is carried out at a temperature of between 55° C. to 60° C. 
     
     
       18. The process according to  claim 12 , wherein the optically active acid is ditoluoyltartaric acid, the solvent is acetone, and the process is carried out at a temperature of between 55° C. to 60° C. 
     
     
       19. The process according to  claim 1 , wherein a catalytic amount of a sulfonic acid is dissolved in the solvent in step (a). 
     
     
       20. The process according to  claim 1 , wherein: 
       R 1  is 2-methoxyphenyl;  
       R 2  and R 3  are each methyl or ethyl; and  
       n is 1,  
       wherein the first solution comprises 1 equivalent of ditoluoyltartaric acid in acetonitrile and the second solution comprises acetonitrile and wherein the process is carried out at a temperature of between 55° C. and 60° C. 
     
     
       21. The process according to  claim 1 , wherein: 
       R 1  is 2-methoxyphenyl;  
       R 2  and R 3  are each methyl; and  
       n is 1,  
       wherein the first solution comprises 1 equivalent of ditoluoyltartaric acid in acetonitrile and the second solution comprises acetonitrile and wherein the process is carried out at a temperature of between 55° C. and 60° C. 
     
     
       22. The process according to  claim 2 , wherein: 
       R 1  is 2-methoxyphenyl;  
       R 2  and R 3  are each methyl or ethyl; and  
       n is 1,  
       wherein the first solution comprises 1 equivalent of (+)-ditoluoyltartaric acid in acetonitrile and the second solution comprises acetonitrile and wherein the process is carried out at a temperature of between 55° C. and 60° C. 
     
     
       23. The process according to  claim 2 , wherein: 
       R 1  is 2-methoxyphenyl;  
       R 2  and R 3  are each methyl; and  
       n is 1,  
       wherein the first solution comprises 1 equivalent of (+)-ditoluoyltartaric acid in acetonitrile and the second solution comprises acetonitrile and wherein the process is carried out at a temperature of between 55° C. and 60° C.